March Approval Madness: OncLive’s Roundup of FDA Decisions in Oncology

In case you missed it, below is your guide to the key regulatory decisions made by the FDA in March 2024, including the data that supported the approvals and expert insights on what they could mean for clinical practice.

Amivantamab Wins Additional Indications in EGFR Exon 20 Insertion+ NSCLC

On March 1, 2024, the FDA approved amivantamab-vmjw (Rybrevant) combined with carboplatin and pemetrexed for the first-line treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) and EGFR exon 20 insertion mutations. The agency also granted full approval to amivantamab for adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations who progressed on or after platinum-based chemotherapy.

Amivantamab plus chemotherapy (n = 153) led to a 60% reduction in the risk of disease progression or death vs chemotherapy alone (n = 155), according to data from the phase 3 PAPILLON trial (NCT04538664). The median progression-free survival (PFS) with the amivantamab combination was 11.4 months (95% CI, 9.8-13.7) compared with 6.7 months (95% CI, 5.6-7.3) with chemotherapy alone (HR, 0.40; 95% CI, 0.30-0.53; P < .0001). The objective response rate was also higher with the addition of amivantamab, at 67% (95% CI, 59%-75%) vs 36% (95% CI, 29%-44%) with chemotherapy alone. Additional data presented at the European Lung Cancer Congress showed that amivantamab plus chemotherapy also significantly extended time to treatment discontinuation (TTD; HR, 0.38; 95% CI, 0.28-0.51; P < .0001) and time to subsequent therapy (TTST; HR, 0.35; 95% CI, 0.25-0.49; P < .0001) compared with chemotherapy alone.

“When we look at PAPILLON, [it is] clearly a positive trial, but really, [it’s] practice changing,” Joshua K. Sabari, MD, told OncLive® in a recent interview. Sabari is an assistant professor in the Department of Medicine at New York University Grossman School of Medicine. “If you think about the primary end point for that study, [amivantamab/chemotherapy] nearly doubled the median PFS for our patients, and really, this is [a] targeted therapy approach or opportunity for our patients with exon 20 insertion–mutant NSCLC [that] I think it really opens up the door for the development of other strategies, novel combination strategies as well as novel agents, in this very rare subpopulation of NSCLC.”

Inotuzumab Ozogamicin Gets Green Light for Pediatric CD22+ B-Cell Precursor ALL

Five days later, the regulatory agency approved inotuzumab ozogamicin (Besponsa) for use in pediatric patients aged 1 year and older with relapsed or refractory, CD22-positive B-cell precursor acute lymphoblastic leukemia (B-ALL). Treatment with the drug led to a complete remission (CR) rate of 42% (95% CI, 28.1%-55.9%) with a median CR duration of 8.2 months (95% CI, 2.5-not evaluable) in patients (n = 53) enrolled in the phase 2 Study WI203581 (NCT02981628). The majority of patients who had a CR also achieved minimal residual disease (MRD) negativity (95.5% by flow cytometry; 86.4% by RQ-PCR).

Previously, in 2017, inotuzumab ozogamicin was approved for use in adults with relapsed or refractory B-ALL based on data from the phase 3 INO-VATE study (NCT01564784).

Zanubrutinib Combo Scores Accelerated Approval for Relapsed/Refractory Follicular Lymphoma

Data from the phase 2 ROSEWOOD trial (NCT03332017) supported the FDA’s decision to grant accelerated approval to zanubrutinib (Brukinsa) paired with obinutuzumab (Gazyva) in patients with relapsed or refractory follicular lymphoma following two or more lines of systemic treatment on March 7, 2024. At a median follow-up of 20.2 months, the doublet (n = 145) elicited an objective response rate of 69% (95% CI, 61%-76%) vs 46% (95% CI, 34%-58%) with single-agent obinutuzumab (n = 72; 2-sided P = .0012); the respective CR rates were 39% and 19%. Moreover, the median duration of response (DOR) with the doublet was NE (95% CI, 25.3-NE) vs 14.0 months (95% CI, 8.2-25.1). The estimated 18-month DOR rate was 69% (95% CI, 58%-78%) in the doublet arm.

“Patients living with follicular lymphoma often experience relapse or do not respond to treatment and need options for treatment during the course of their illness,” Christopher Flowers, MD, Division Head of Cancer Medicine and Chair of the Department of Lymphoma/Myeloma, at The University of Texas MD Anderson Cancer Center, in Houston, stated in a press release. “The findings from the ROSEWOOD trial highlight the significant clinical advantage of treating patients who experience relapse or have refractory follicular lymphoma with zanubrutinib plus obinutuzumab.”

In November 2023, zanubrutinib plus obinutuzumab was granted marketing authorization by the European Commission for use in adult patients with relapsed or refractory follicular lymphoma after at least two prior lines of systemic therapy. This decision was also based on findings from ROSEWOOD.

FDA OKs Nivolumab Plus Chemotherapy for Unresectable or Metastatic Urothelial Carcinoma

On the same day, the regulatory agency gave the green light to the combination of nivolumab (Opdivo) and cisplatin/gemcitabine for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma based on data from the phase 3 CheckMate 901 study (NCT03036098). The chemoimmunotherapy regimen (n = 304) significantly improved overall survival (OS) vs chemotherapy alone (n = 304), at a median OS of 21.7 months (95% CI, 18.6-26.4) and 18.9 months (95% CI, 14.7-22.4), respectively (HR, 0.78; 95% CI, 0.63-0.96; 2-sided P = .0171). Nivolumab plus chemotherapy also improved PFS over chemotherapy alone, at a median of 7.9 months (95% CI, 7.6-9.5) and 7.6 months (95% CI, 6.0-7.8), respectively (HR, 0.72; 95% CI, 0.59-0.88; 2-sided, P = .0012). The respective ORRs were 57.6% (95% CI, 51.8%-63.2%) and 43.1% (95% CI, 37.5%-48.9%), respectively; the median DORs were 9.5 months (95% CI, 7.6-15.1) and 7.3 months (95% CI, 5.7-8.9), respectively.

CheckMate 901 represents one of the first studies to demonstrate a survival benefit with the combination of immunotherapy and cisplatin-based chemotherapy in the frontline setting for cisplatin-eligible patients with urothelial carcinoma, according to Abhishek Tripathy, MD, who is a genitourinary medical oncologist at City of Hope in Duarte, California. He added that it will be important to compare the regimen’s utilization with other combination approaches like enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda).

In October 2023, the European Medicines Agency validated a type II variation application for nivolumab plus cisplatin-based chemotherapy in the frontline treatment of adult patients with unresectable or metastatic urothelial carcinoma.

Tislelizumab Wins Approval for Advanced or Metastatic ESCC Following Chemotherapy

On March 14, 2024, the FDA approved tislelizumab-jsgr (Tevimbra) for use as a monotherapy in adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) after previous systemic chemotherapy that did not include a PD-1 or PD-L1 inhibitor. The decision was based on findings from the phase 3 RATIONALE 302 study (NCT03430843) in which treatment with the agent (n = 256) led to a median OS of 8.6 months (95% CI, 7.5-10.4) vs 6.3 months (95% CI, 5.3-7.0) with chemotherapy (n = 256; HR, 0.70; 95% CI, 0.57-0.85; P = .0001). The 6-month OS rates were 62.3% and 51.8% and the 12-month OS rates were 37.4% and 23.7%.

Previously, in July 2022, the regulatory agency deferred action on the biologics license application (BLA) seeking the approval of tislelizumab in the second-line setting for this population citing the inability to conduct required inspections in China due to travel restrictions linked with COVID-19.

“Patients diagnosed with advanced or metastasized ESCC, the most common histologic subtype of esophageal cancer, often progress following initial therapy and are in need of new options,” Syma Iqbal, MD, associate professor of clinical medicine and section chief of Gastrointestinal Oncology in the Division of Medical Oncology and cancer physician in chief at Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, stated in a press release. “The RATIONALE 302 trial showed that patients with previously treated ESCC who received [tislelizumab] saw a clinically meaningful survival benefit, highlighting its potential as an important treatment option for these patients.”

In September 2023, the European Commission approved single-agent tislelizumab for use in adult patients with unresectable, locally advanced or metastatic ESCC after prior platinum-based chemotherapy. In the same month, the FDA accepted for review a BLA seeking the approval of tislelizumab in the first-line setting for patients with unresectable, recurrent, locally advanced or metastatic ESCC based on data from the phase 3 RATIONALE 306 study (NCT03783442), which showed that tislelizumab plus chemotherapy (n = 326) produced a median OS of 17.2 months (95% CI, 15.8-20.1) vs 10.6 months (95% CI, 9.3-12.1) with placebo plus chemotherapy (n = 323; stratified HR, 0.66; 95% CI, 0.54-0.80; P < .0001).

Lisocabtagene Maraleucel Becomes Only CAR T Approved for Relapsed/Refractory CLL or SLL

On the same day, the CAR T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi) received FDA accelerated approval for use in adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have previously received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

The decision was supported by findings from the phase 1/2 TRANSCEND CLL 004 study (NCT03331198). Liso-cel induced a complete response (CR) rate of 20% (95% CI, 11.1%-31.8%); those achieved the CR experienced a median DOR that was not yet reached (NR; 95% CI, 15 months-NR). The 12-month DOR rate was 100% and the 18-month DOR was 87.5% (95% CI, 38.7%-98.1%). Moreover, the ORR achieved with liso-cel was 45% (95% CI, 32.3%-57.5%) and the median DOR was 35.3 months (95% CI, 12.4-NR).

“We are seeing that the response rate [with liso-cel] is decent and that approximately 20% of patients go into complete, deep remission,” Saad J. Kenderian, MB, CHB, a consultant in the Division of Hematology, Department of Internal Medicine, Department of Immunology, and Department of Molecular Medicine at the Mayo Clinic in Rochester, Minnesota, told OncLive. Kenderian is also an assistant professor of oncology, immunology, and medicine Arguably, [these [patients] are potentially cured of CLL. “We know that in [this disease], some of the first patients who were treated with CAR T-cell therapy are in remission more than 10 years later. Also, some of our patients who are treated with liso-cel on the trial are in remission 3 or 4 years later. We are excited about this [approval] and excited to be able to use [this agent] in more patients.”

Important safety information for liso-cel include boxed warnings regarding cytokine release syndrome, neurologic toxicities, and secondary hematologic malignancies.

Ponatinib Plus Chemo Scores Accelerated Approval for Newly Diagnosed Ph+ ALL

The FDA granted another accelerated approval a few days later, on March 19, 2024, to ponatinib (Iclusig) paired with chemotherapy for use in adult patients with newly diagnosed, Philadelphia chromosome-positive acute lymphoblastic leukemiabased on data from the phase 3 PhALLCON study (NCT03589326). The ponatinib regimen (n = 164) induced a MRD-negative CR rate of 30% at the end of induction treatment vs 12% with imatinib (Gleevec) paired with chemotherapy (n = 81; risk difference, 0.18; 95% CI, 0.08-0.28; P = .0004).

Additional findings indicated that 79% and 63% of patients, respectively, achieved a CR at the end of induction. In a subgroup of those who had not received prephase therapy, MRD-negative CR was achieved by 31% and 16% of those in the ponatinib and imatinib arms, respectively, and 84% and 61% of patients achieved a CR at the end of induction.

The most common toxicities included hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/elevated lipase, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias. The label has boxed warnings with regard to arterial occlusive events, venous thromboembolic events, heart failure, and hepatotoxicity.

“This is the first time we have a frontline TKI approved in Ph-positive ALL. From now on, we have a new SOC,” Elias Jabbour, MD, a professor of medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, told OncLive. In his interview he underscored that not only does the regulatory decision introduce ponatinib as the first and only TKI to be approved for use in the first-line setting of this disease with chemotherapy, but it also represents a notable milestone as the first FDA authorization supported by the assessment of MRD after induction.

Mirvetuximab Soravtansine Gets Full Approval for FRα+ Platinum-Resistant Ovarian Cancer

On March 22, 2024, the FDA granted regular approval to mirvetuximab soravtansine-gynx (Elahere)for use adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have previously received one to three systemic treatment regimens. The decision was based on findings from the phase 3 MIRASOL study (NCT04209855). The median OS with mirvetuximab soravtansine (n = 227) was 16.5 months (95% CI, 14.5-24.6) vs 12.7 months (95% CI, 10.9-14.4) with investigator’s choice of chemotherapy (n = 226; HR, 0.67; 95% CI, 0.50-0.88; P = .0046).

The antibody-drug conjugate also improved PFS vs chemotherapy, at a median of 5.6 months (95% CI, 4.3-5.9) vs 4.0 months (95% CI, 2.9-4.5), respectively (HR, 0.65; 95% CI, 0.52-0.81; P < .0001). The ORR with mirvetuximab soravtansine was 42% (95% CI, 36%-49%) vs 16% (95% CI, 12%-22%) with chemotherapy (P < .0001).

In an interview with OncLive, Gottfried Konecny, MD, lead clinician, gynecologic oncology, Department of Medicine, University of California, Los Angeles noted that the MIRASOL trial underscores the promising therapeutic potential of mirvetuximab soravtansine in addressing the pressing clinical challenges associated with platinum-resistant recurrent ovarian cancer. He added that the observed improvements in PFS, OS, and ORR signify a significant advancement in the treatment of this subgroup of patients with a challenging disease.

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